Synergistic interaction between adenosine A2A and glutamate mGlu5 receptors:: Implications for striatal neuronal function
Synergistic interaction between adenosine A2A and glutamate mGlu5 receptors:: Implications for striatal neuronal function
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DOI：
10.1073/pnas.172393799
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发表时间：
2002-09-03
影响因子：
11.1
通讯作者：
Ciruela, F
中科院分区：
文献类型：
--
作者：
Ferré, S;Karcz-Kubicha, M;Ciruela, F
腺苷A2 A受体和I组代谢型谷氨酸受体在纹状体氨基丁酸（GABA）能神经元中共表达的生理意义是有趣的。在这里，我们提供了在体外和体内的腺苷和谷氨酸之间的协同作用的基础上亚型5代谢型谷氨酸（mGluR 5）和腺苷A2 A（A2 AR）受体/受体相互作用的证据。共聚焦激光显微镜观察到A2 AR和mGluR 5在非透性人胚肾（HEK）-293细胞中瞬时共转染，在膜水平上共定位。通过对来自共转染HEK-293细胞的膜制剂中的Flag-A2 AR或血凝素-mGluR 5的免疫沉淀物以及大鼠纹状体膜制剂中的天然A2 AR和mGluR 5的免疫沉淀物进行Western印迹，证明了含有A2 AR和mGluR 5的复合物。在共转染的HEK-293细胞中，A2 AR/mGluR 5共刺激对细胞外信号调节激酶1/2磷酸化和c-fos表达具有协同作用。在第二信使水平（cAMP积累和细胞内钙动员）没有观察到协同效应。因此，对纹状体部分的c-fos表达和对抗苯环利定诱导的运动激活的协同作用，也证明了后中央共同管理的A2 AR和mGluR 5激动剂与完整的多巴胺能神经支配的大鼠。结果表明，需要一个功能mGluR 5/A2 AR的相互作用，以克服众所周知的强大的紧张性抑制作用的多巴胺纹状体腺苷A2 AR功能。
The physiological meaning of the coexpression of adenosine A2A receptors and group I metabotropic glutamate receptors in aminobutyric acid (GABA)ergic striatal neurons is intriguing. Here we provide in vitro and in vivo evidence for a synergism between adenosine and glutamate based on subtype 5 metabotropic glutamate (mGluR5) and adenosine A2A (A2AR) receptor/receptor interactions. Colocalization of A2AR and mGluR5 at the membrane level was demonstrated in nonpermeabilized human embryonic kidney (HEK)-293 cells transiently cotransfected with both receptors by confocal laser microscopy. Complexes containing A2AR and mGluR5 were demonstrated by Western blotting of immunoprecipitates of either Flag-A2AR or hemagglutinin-mGluR5 in membrane preparations from cotransfected HEK-293 cells and of native A2AR and mGluR5 in rat striatal membrane preparations. In cotransfected HEK-293 cells a synergistic effect on extracellular signal-regulated kinase 1/2 phosphorylation and c-fos expression was demonstrated upon A2AR/mGluR5 costimulation. No synergistic effect was observed at the second messenger level (cAMP accumulation and intracellular calcium mobilization). Accordingly, a synergistic effect on c-fos expression in striatal sections and on counteracting phencyclidine-induced motor activation was also demonstrated after the central coadministration of A2AR and mGluR5 agonists to rats with intact dopaminergic innervation. The results suggest that a functional mGluR5/A2AR interaction is required to overcome the well-known strong tonic inhibitory effect of dopamine on striatal adenosine A2AR function.